1. Field of the Invention
This invention relates to the field of medical devices, such as stents. More particularly, this invention is directed to coatings which include polycationic peptides such as polymers and/or oligomers of L-arginine.
2. Description of the State of the Art
In the field of medical technology, there is frequently a necessity to administer a therapeutic substance locally. To provide an efficacious concentration to the treatment site, systemic administration of medication often produces adverse or toxic side effect for the patient. Local delivery is a preferred method in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Thus, local delivery produces fewer side effects and achieves more effective results. For the treatment of vascular occlusions, such as restenosis, stents are being modified to administer therapeutic substances locally. One method of medicating a stent is with the use of a polymer coating impregnated with a therapeutic substance. The coating allows for the sustained release of the substance at the treatment site. L-arginine, or polypeptide oligomeric derivatives or analogs thereof, for example, those containing 5 to 20 amino acid units are one example of a therapeutic substance that can be used in conjunction with a stent.
L-arginine is a known precursor of endothelium derived nitric oxide (NO). NO is synthesized from L-arginine, or its polymeric and/or oligomeric derivatives, by the enzyme NO synthase oxygenase, a homodimeric flavo-hemoprotein that catalyzes the 5-electron oxidation of L-arginine to produce NO and L-citrulline. Among other therapeutic properties, NO regulates vascular tone, inhibits platelet aggregation, and inhibits vascular smooth muscle proliferation. These therapeutic properties are believed to contribute to the reduction or elimination of neo-intimal hyperplasia in vascular injury models.
U.S. Pat. No. 5,861,168 to Cooke et al. teaches that NO activity is reduced after vascular injury. Cooke et al. also teach that administering L-arginine as the NO precursor helps to restore vascular NO activity in patients with endothelial vasodilator dysfunction due to restenosis. It has been also taught that oligomeric peptides comprising 6 to 15 units of L- or D-arginine can be effective transfectors of cells (see, Mitchell, et al., J. Peptide Res., vol. 56, p. 318 (2000)) and, using a rabbit vein-graft model, it has been demonstrated that oligomers of L- or D-arginine can inhibit vascular smooth cell proliferation by efficiently transfecting cells. See, Uemura, et al., Circulation, vol. 102, p. 2629 (2000). Using the rabbit model, it has also been shown that intramural administration of L-arginine inhibits lesion formation in a hypercholesterolemic balloon injury. See, Schwarzacher et al. Circulation, vol. 95, p. 1863 (1997).
Due to the strong basicity of the guanidinium group, —NH—C(NH2)═NH, L-arginine is highly cationic. For example, the heptamer of L-arginine has the pKa=13.2. This high degree of polarity causes L-arginine, or its polymers and/or oligomers, to be practically insoluble in most organic solvents having the Hildebrand solubility parameter δ≦12.7 (cal/cm3)1/2.
The term “Hildebrand solubility parameter” refers to a parameter measuring the cohesion of a substance. The δ parameter is determined as follows:δ=(ΔE/V)1/2 
where δ=solubility parameter, (cal/cm3)1/2;                ΔE=energy of vaporization, cal;        V=molar volume, cm3         
The more polar the solvent, the higher its cohesion due to the existence of strong van der Waals forces. Consequently, it takes more energy to vaporize more polar substances, resulting in the higher numerical value of δ.
Thus, L-arginine or its polymers and/or oligomers are believed to be soluble only in water (δ=23.4 (cal/cm3)1/2)(as much as 15% by weight concentration in water can be achieved for the heptamer of L-arginine) and have some limited solubility only in very polar solvents having high values of δ, for example, formamide (δ=19.2 (cal/cm3)1/2), methanol (δ=14.5(cal/cm3)1/2), or ethanol (δ=12.7 (cal/cm3)1/2).
While polycationic peptides, such as L-arginine, are practically insoluble in many organic solvents, the polymers from which the stent coatings are made are soluble in organic solvents but not water. The incompatibility of solubility of the polymer and L-arginine in a common solvent or common mixture of solvents can lead to poor coating characteristics and poor release profile of the peptide from the coating. Furthermore, the high degree of solubility of polycationic peptides in water tends to increase the in vivo rate of release of the peptides, which may be undesirable. Polycationic peptides are essentially incompatible with hydrophobic polymers which are commonly used to coat a stent. The embodiments of the present invention address these and other deficiencies.